This proposal addresses those factors which influence neuronal form and connectivity. In particular the relationship between neurite outgrowth and the matrix of connections that a given neuron posseses will be investigated. We have found that adult neurons are responsive to transmitter in a unique way, that is transmitters can act as regulators of development and neuroplasticity by regulating the behavior of neuronal growth cones. In addition to other transmitter substances which alter growth cone behavior, serotonin, which was originally eluciated as regulating growth cone behavior in vitro, appears to play a role in neuroembryology. Furthermore, neuronal activity, that is the generation of action potentials, has a profound influence on neurite outgrowth. These results pose a class of questions regarding the autoregulation of neuronal form and connectivity. That is, does the activity of neurons bias their ability to grow and hence form synapses and conversely, once formed, do synaptic connections alter neuronal activity and in a feedback fashion, regulate the further synapse-forming potential of each component neuron? This activity could be either in the form of action potentials generated by an individual neuron or by release of neurotransmitter from adjacent neurons or from branches of the original neuron. In light of the results to date, we will evaluate the effect of electrical activity on synapse formation. We will also examine the effects of potential targets using cell culture methods addressing whether targets can alter neuronal activity and thereby alter growth and connectivity. We are now examining "classical" chemical synapses in culture to address factors governing chemical synaptogenesis. The majority of this work will be performed in cell culture where individual identified neuronal behavior can be observed without the complexity of the in vivo environment of the buccal ganglia. Complementary experiments in situ will parallel the work in culture, providing a whole animal context in which to relate the results observed in cell culture.